Title

Theoretical insights on the binding of isoniazid to the active site residues of mycobacterium tuberculosis catalase-peroxidase

College

College of Science

Department/Unit

Chemistry

Document Type

Article

Source Title

Tuberculosis

Volume

114

First Page

61

Last Page

68

Publication Date

1-1-2019

Abstract

Isoniazid (INH) is known to cause the exclusive lethal action to Mycobacterium tuberculosis (M. tb.) cells because of the pathogen's own catalase-peroxidase (katG) enzyme that converts INH to a very reactive radical. Thus, in order to gain insights on the interaction of INH with the individual active site residues (Res) of katG, this study presents a computational approach via molecular docking and density functional theory (DFT) using augmented models to study the individual INH-Res interactions. Seven amino acid residues directly interacts with INH: Arg104, Asp137, His108, Ile228, Trp107, Tyr229, and Val230. The residues with the highest interaction energies are Arg104 (−39.64 kcal/mol) and Asp137 (−32.85 kcal/mol) mainly due to strong ion-dipole and H-bonding interactions present in the complexes, while the weakest interaction was observed for Ile228 (−13.78 kcal/mol). Molecular electrostatic potential surface revealed complementary regions for dipole interactions and charge distribution analysis further shows that INH generally donates electrons to the residues. The results in this study agrees with the previous experimental findings and provides new insights into the catalase dependent activation of INH and the methods presented may be valuable in the study of biological metabolism of molecules. © 2018 Elsevier Ltd

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Digitial Object Identifier (DOI)

10.1016/j.tube.2018.11.005

Disciplines

Chemistry

Keywords

Isoniazid; Mycobacterium tuberculosis; Drug resistance in microorganisms; Computational chemistry

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